Neovascularization is a phenomenon in which a new blood vessel network is formed from an existing vessel, which is predominantly observed in microvessels. Neovascularization is a physiological phenomena and essential for angiogenesis during the embryonic stage but is not observed in adults except for limited sites such as endometrium and follicle and limited periods such as a course of healing of wounds. However, pathologic neovascularization is observed in diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, plaque psoriasis, and atherosclerosis and is associated closely with pathologic progress of each of the diseases. The neovascularization is regulated by a balance between a promoting factor and a suppressing factor, and it is considered that the neovascularization occurs due to disruption of the balance (see Non-Patent Publication 1 and Non-Patent Publication 2).
The vascular endothelial growth factor (hereinafter, referred to as “VEGF”) is a factor that promotes construction of a capillary vessel network by way of proliferation, migration, and tube formation of vascular endothelial cells by specifically acting on receptors (Flt-1, KDR/Flk-1, etc.) existing on a surface of vascular endothelial cells and has a remarkably important role in occurrence of neovascularization. Therefore, many trials for treating the diseases associated with neovascularization by controlling occurrence of neovascularization through inhibition of VEGF have been reported. Examples of drugs to be used for such treatment include indolin-2-one derivatives (see Patent Publication 1), phthalazine derivatives (see Patent Publication 2), quinazoline derivatives (see Patent Publication 3), anthranilamide derivatives (see Patent Publication 4), the 2-aminonicotinic acid derivatives (see Patent Publication 5), 4-pyridylalkylthio derivatives (see Patent Publication 6), and the like.
Meanwhile, since compounds having an oxadiazole ring or a thiadiazole ring exhibit useful bioactivity, applications of the compounds to many pharmaceutical products and the like have been tried. Among the applications, each of the oxadiazole derivatives reported in Patent Publication 7 and Non-Patent Publications 3 and 4 is proved to have neovascularization inhibitory activity by way of the inhibition of VEGF receptor tyrosine kinase. Each of the compounds disclosed in the publications is characterized by having a 4-pyridylalkylamino group or a 4-pyridylethyl group. However, synthesis and neovascularization inhibitory activity of the compounds having the 4-pyridylalkyloxy group, 4-pyridylalkylthio group, or the like are not disclosed at all.    Non-Patent Publication 1: Molecular Medicine, vol. 35, Extra Edition, “Molecular Mechanism of Symptom and Pathology”, Nakayama Shoten, 73-74 (1998)    Non-Patent Publication 2: Extra Edition of Protein, Nucleic Acid, and Enzyme, “Forefront Drug Development”, Kyoritsu Shuppan, 118, 2-1187 (2000)    Non-Patent Publication 3: Bioorg, Med. Chem. Lett., 16 (5), 1440-1444 (2006)    Non-Patent Publication 4: Bioorg, Med. Chem. Lett., 16 (7), 1913-1919 (2006)    Patent Publication 1: International Publication WO98/50356    Patent Publication 2: International Publication WO98/35958    Patent Publication 3: International Publication WO97/30035    Patent Publication 4: International Publication WO00/27819    Patent Publication 5: International Publication WO01/55114    Patent Publication 6: International Publication WO04/078723    Patent Publication 7: International Publication WO04/052280